Valdecoxib achieves maximal plasma concentrations in approximately 3 hours. The absolute bioavailability of valdecoxib is 83% following oral administration of BEXTRA (valdecoxib) compared to intravenous infusion of valdecoxib.

Dose proportionality was demonstrated after single doses (1 - 400 mg) of valdecoxib. With multiple doses (up to 100 mg/day for 14 days), valdecoxib exposure as measured by the AUC, increases in a more than proportional manner at doses above 10 mg BID. Steady state plasma concentrations of valdecoxib are achieved by day 4. The steady state pharmacokinetic parameters of valdecoxib in healthy male subjects are shown in Table 1.

Table 1 Mean (SD) Steady State Pharmacokinetic Parameters

Steady State Pharmacokinetic Parameters after Valdecoxib 10 mg Once Daily for 14 Days

Healthy Male Subjects (n=8, 20 to 42 yr.)

AUC(0-24hr) (hr·ng/mL)

1479.0 (291.9)

Cmax (ng/mL)

161.1 (48.1)

Tmax (hr)

2.25 (0.71)

Cmin (ng/mL)

21.9 (7.68)

Elimination Half-life (hr)

8.11 (1.32)

No clinically significant age or gender differences were seen in pharmacokinetic parameters that would require dosage adjustments.

Effect of Food and Antacid

BEXTRA (valdecoxib) can be taken with or without food. Food had no significant effect on either the peak plasma concentration (Cmax) or extent of absorption (AUC) of valdecoxib when BEXTRA (valdecoxib) was taken with a high fat meal. The time to peak plasma concentration (Tmax), however, was delayed by 1-2 hours. Administration of BEXTRA (valdecoxib) with antacid (aluminum/magnesium hydroxide) had no significant effect on either the rate or extent of absorption of valdecoxib.

Distribution

Plasma protein binding for valdecoxib is about 98% over the concentration range (21-2384 ng/mL). Steady state apparent volume of distribution (Vss/F) of valdecoxib is approximately 86 L after oral administration. Valdecoxib and its active metabolite preferentially partition into erythrocytes with a blood to plasma concentration ratio of about 2.5:1. This ratio remains approximately constant with time and therapeutic blood concentrations.

In humans, valdecoxib undergoes extensive hepatic metabolism involving both P450 isoenzymes (3A4 and 2C9) and non-P450 dependent pathways (i.e., glucuronidation). Concomitant administration of BEXTRA (valdecoxib) with known CYP 3A4 and 2C9 inhibitors (e.g., fluconazole and ketoconazole) can result in increased plasma exposure of valdecoxib (see PRECAUTIONSDrug Interactions). One active metabolite of valdecoxib has been identified in human plasma at approximately 10% the concentration of valdecoxib. This metabolite, which is a less potent COX-2 specific inhibitor than the parent, also undergoes extensive metabolism and constitutes less than 2% of the valdecoxib dose excreted in the urine and feces. Due to its low concentration in the systemiccirculation, it is not likely to contribute significantly to the efficacy profile of BEXTRA (valdecoxib) .

Excretion

Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-glucuronide. The apparent oral clearance (CL/F) of valdecoxib is about 6 L/hr. The mean elimination half-life (T1/2) ranges from 8-11 hours, and increases with age.

Special Populations

Geriatric

In elderly subjects (> 65 years), weight-adjusted steady state plasma concentrations (AUC(0-12hr)) are about 30% higher than in young subjects. No dose adjustment is needed based on age.

BEXTRA (valdecoxib) has not been investigated in pediatric patients below 18 years of age.

Race

Pharmacokinetic differences due to race have not been identified in clinical and pharmacokinetic studies conducted to date.

Hepatic Insufficiency

Valdecoxib plasma concentrations are significantly increased (130%) in patients with moderate (Child-Pugh Class B) hepatic impairment. In clinical trials, doses of BEXTRA (valdecoxib) above those recommended have been associated with fluid retention. Hence, treatment with BEXTRA (valdecoxib) should be initiated with caution in patients with mild to moderate hepatic impairment and fluid retention. The use of BEXTRA (valdecoxib) in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended.

The pharmacokinetics of valdecoxib have been studied in patients with varying degrees of renal impairment. Because renal elimination of valdecoxib is not important to its disposition, no clinically significant changes in valdecoxib clearance were found even in patients with severe renal impairment or in patients undergoing renal dialysis. In patients undergoing hemodialysis the plasma clearance (CL/F) of valdecoxib was similar to the CL/F found in healthy elderly subjects (CL/F about 6 to 7 L/hr.) with normal renal function (based on creatinine clearance).

NSAIDs have been associated with worsening renal function and use in advanced renal disease is not recommended (see PRECAUTIONS Renal Effects).

Valdecoxib undergoes both P450 (CYP) dependent and non-P450 dependent (glucuronidation) metabolism. In vitro studies indicate that valdecoxib is not a significant inhibitor of CYP 1A2, 3A4, or 2D6 and is a weak inhibitor of CYP 2C9 and a weak to moderate inhibitor of CYP 2C19 at therapeutic concentrations. The P450-mediated metabolic pathway of valdecoxib predominantly involves the 3A4 and 2C9 isozymes. Using prototype inhibitors and substrates of these isozymes, the following results were obtained. Coadministration of a known inhibitor of CYP 2C9/3A4 (fluconazole) and a CYP 3A4 inhibitor (ketoconazole) enhanced the total plasma exposure (AUC) of valdecoxib. Coadministration of valdecoxib with a CYP 3A4 inducer (phenytoin) decreased total plasma exposure (AUC) of valdecoxib. (See PRECAUTIONSDrugInteractions.)

Coadministration of valdecoxib with warfarin (a CYP 2C9 substrate) caused a small, but statistically significant increase in plasma exposures of R-warfarin and S-warfarin, and also in the pharmacodynamic

Coadministration of valdecoxib with dextromethorphan (a CYP 2D6/3A4 substrate) resulted in an increase in dextromethorphan plasma levels above those seen in subjects with normal levels of CYP 2D6. Even so these levels were almost 5-fold lower than those seen in CYP 2D6 poor metabolizers (See PRECAUTIONSDrug Interactions.)

Coadministration of valdecoxib with phenytoin (a CYP 2C9/2C19 substrate) did not affect the pharmacokinetics of phenytoin.

Coadministration of valdecoxib, or its injectable prodrug, with substrates of CYP 2C9 (propofol) and CYP 3A4 (midazolam, alfentanil, fentanyl) did not inhibit the metabolism of these substrates.

BEXTRA (valdecoxib) was evaluated for treatment of the signs and symptoms of osteoarthritis of the knee or hip, in five double-blind, randomized, controlled trials in which 3918 patients were treated for 3 to 6 months. BEXTRA (valdecoxib) was shown to be superior to placebo in improvement in three domains of OA symptoms: (1) the WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, a composite of pain, stiffness and functional measures in OA, (2) the overall patient assessment of pain, and (3) the overall patient global assessment. The two 3-month pivotal trials in OA generally showed changes statistically significantly different from placebo, and comparable to the naproxen control, in measures of these domains for the 10 mg/day dose. No additional benefit was seen with a valdecoxib 20-mg daily dose.

BEXTRA (valdecoxib) demonstrated significant reduction compared to placebo in the signs and symptoms of RA, as measured by the ACR (American College of Rheumatology) 20 improvement, a composite defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five: patient global, physician global, patient pain, patient function assessment, and C-reactive protein (CRP). BEXTRA (valdecoxib) was evaluated for treatment of the signs and symptoms of rheumatoid arthritis in fourdouble-blind, randomized, controlled studies in which 3444 patients were treated for 3 to 6 months. The two 3-month pivotal trials compared valdecoxib to naproxen and placebo. The results for the ACR20 responses in these trials are shown below (Table 2). Trials of BEXTRA (valdecoxib) in rheumatoid arthritis allowed concomitant use of corticosteroids and/or disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate, gold salts, and hydroxychloroquine. No additional benefit was seen with a valdecoxib 20-mg daily dose.

Table 2 ACR20 Response Rate (%) in Rheumatoid Arthritis

Study 1

Study 2

BEXTRA 10 mg/day

49%**

(103/209)

46%**

(103/226)

BEXTRA 20 mg/day

48%**

(102/212)

47%*

(103/219)

Naproxen 500 mg BID

44%*

(100/225)

53%**

(115/219)

Placebo

32%

(70/222)

32%

(71/220)

* p<0.01; ** p< 0.001 compared to placebo

Primary Dysmenorrhea

BEXTRA was compared to naproxen sodium 550 mg in two placebo-controlled studies of women with moderate to severe primary dysmenorrhea. The onset of analgesia was within 60 minutes for BEXTRA 20 mg. The onset, magnitude, and duration of analgesic effect with BEXTRA 20 mg were comparable to naproxen sodium 550 mg.

Safety Studies

Gastrointestinal (GI) Endoscopy Studies with Therapeutic Doses: Scheduled upper GI endoscopic evaluations were performed with BEXTRA at doses of 10 and 20 mg daily in over 800 OA patients who were enrolled into two randomized 3-month studies using active comparators and placebo controls (Study 3 and Study 4). These studies enrolled patients free of endoscopic ulcers at baseline and compared rates of endoscopic ulcers, defined as any gastroduodenal ulcer seen endoscopically provided it was of "unequivocal depth" and at least 3 mm in diameter.

In both studies, BEXTRA 10 mg daily was associated with a statistically significant lower incidence of endoscopic gastroduodenal ulcers over the study period compared to the active comparators.

BEXTRA 40 mg daily and 80 mg daily were associated with a statistically significant lower incidence of endoscopic gastroduodenal ulcers over the study period compared to naproxen. The incidence of renal events was significantly different between the BEXTRA 80 mg daily group and naproxen. The clinical relevance of renal events observed with supratherapeutic doses (4 to 8 times the recommended therapeutic dose) of BEXTRA is not known (see PRECAUTIONS Renal Effects).

Renal Safety at the Therapeutic Chronic Dose:The renal effects of valdecoxib compared with placebo and conventional NSAIDs were also assessed by prospectively designed pooled analyses of renal events data (see definition above - Supratherapeutic Doses) from five placebo- and active -controlled 12-week arthritis trials that included 995 OA or RA patients given valdecoxib 10 mg daily. The incidence of renal events observed in this analysis with valdecoxib 10 mg daily (3%), ibuprofen 800 mg TID (7%), naproxen 500 mg BID (2%) and diclofenac 75 mg BID (4%) were significantly higher than placebo-treated patients (1%). In all treatment groups, the majority of renal events were either due to the occurrence of edema or worsening BP.